High-risk human papillomavirus (HPV) types, particularly HPV16, are causally associated with human malignancies including cervical and vaginal cancers in women (zur Hausen H, 2002). New prophylactic HPV vaccines can prevent infections by a subset of these HPVs; however, they will not eliminate pre-existing HPV infections, new infections by high-risk HPVs not targeted by the vaccines, or cervical cancers and precancerous lesions that arise from those HPV infections (Roden and Wu, 2006). Traditional therapeutic approaches (for example, surgery, radiotherapy, and chemotherapy) are of limited value to patients with advanced or recurrent cervical cancer. Consequently, cervical cancer remains the second leading cause of death by cancer among women worldwide (zur Hausen H, 2002; Roden and Wu, 2006). New, more effective therapeutic strategies are clearly needed. Herein, a potent new therapeutic approach that not only effectively treats preexisting cervical and vaginal cancers but also can prevent their onset is identified.
The uterine cervix is highly responsive to steroidal hormones such as estrogen. Correspondingly, cervical cancers most commonly arise in the 3rd-5th decades, which typically correspond to the pre-menopausal period of life in women (Cline, 2004). Furthermore, use of oral contraceptives or high parity has been shown to significantly increase the risk for cervical cancer in HPV-infected women (Moreno et al., 2002; Munoz N et al., 2002). These observations raise the possibility that steroidal hormones such as estrogen might affect cancers of the cervix, much like that of other hormonally responsive female organs (Cline, 2004; Jordan, 2007). Estrogen replacement therapy alone, however, does not increase the risk for cervical cancer, and tamoxifen, a well-known estrogen receptor antagonist in the breast, has no beneficial effect on cervical cancer (Bigler et al., 2004; Persson et al., 1996). Unfortunately, neither of these studies controlled for infections with high-risk HPVs that are prerequisite for cervical cancer (zur Hausen H, 2002; Roden and Wu, 2006). Furthermore, tamoxifen has an estrogen receptor (ER) agonistic rather than antagonistic effect in the human cervix (Friedrich et al., 1998). Studies have shown a protective effect on cervical cancer by indole-3-carbinol, a compound found in cruciferous vegetables that favorably alters the metabolism of estrogen; however, this drug has also been shown to inhibit the genesis of other tumors that are not believed to depend upon estrogen (Aggarwal and Ichikawa, 2005; Jin et al., 1999; Bell et al., 2000). Thus, the evidence for or against a role of estrogen in cervical carcinogenesis in humans has been limited in nature and inconclusive.
To elucidate mechanisms by which HPV oncogenes promote cervical cancer and by which cofactors contribute to cervical carcinogenesis, we have generated transgenic mouse models that express HPV16 E6 and/or E7 under the control of human keratin 14 promoter that drives gene expression in stratified squamous epithelia, natural targets for HPV infection. The progressive disease that arises in these mouse models recapitulates various aspects of human cervical disease, including the multiple stages of cervical carcinogenesis, the anatomical location and histopathological nature of the cancers, and the expression patterns of various biomarkers (Brake et al., 2003; Elson et al., 2000), validating the relevance of these preclinical models to cervical disease in women. Using these mouse models, we have demonstrated that estrogen is required for development of cervical cancer and that estrogen receptor alpha (ERα) is crucial for the development of atypical squamous metaplasia (ASM), which has been proposed to be the very first step of cervical carcinogenesis preceding the development of cervical intraepithelial neoplasia (CIN), a precancerous cervical lesion that can progress to cervical cancer (Elson et al., 2000; Brake and Lambert, 2005; Chung et al., 2008; Shai et al., 2007; Arbeit et al., 1996; Riley RR, et al. 2003). It is still unclear, however, whether ER-α is crucial for the progression of CIN lesions to invasive cancer and maintenance of cervical cancer. Herein, it is demonstrated that inhibition of ER is effective in both treating and preventing cervical cancer in mice.